A substantial body of evidence indicates that peripheral opioid peptides and their receptors have a major physiological role in the regulation of gut motility. Consequently, gastrointestinal disorders such as idiopathic constipation and irritable bowel syndrome may relate to a dysfunction of opioid receptor mediated control, and agents which act as antagonists for these receptors may benefit a patient suffering from such a dysfunction.
The N-substituted piperidines, prepared using the process and intermediates of this invention are useful as peripherally-selective opioid antagonists. One particularly desirable 3,4,4-trisubstituted-piperidinyl-N-alkylcarboxylate is (2S,3R,4R)([[2-[[4-(3-hydroxyphenyl)-3,4-dimethyl-1piperidinyl]methyl]-1-o xo-3-phenylpropyl]amino]acetic acid (1). ##STR1##
A generic process to prepare (.alpha.S,3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-.alpha.-(phenylmethyl)-1 -piperidine propanoic acid ethyl ester (2), a useful intermediate for the preparation of 1, is known to the skilled artisan. Zimmerman describes this process in U.S. Pat. No. 5,250,542 (hereincorporated by reference). However, this process produces a mixture of stereoisomeric products which prevents its utilization in a practical commercial process. The preparation of the desired compound of Formula 1 requires a tedious chromatographic separation with only 13% yield for the isomer separation. Further, each intermediate is isolated as a "gum-like" product due to the presence of the undesired isomer. The "gum-like" product precludes purification of any intermediate without chromatography and is highly undesirable for commercial purposes.
The process of this invention now provides a synthetic route which will provide crystalline intermediates, without epimerization to facilitate the commercial preparation of 1 and C.sub.1 -C.sub.6 alkyl esters thereof. Additionally, the process of this invention produces a crystalline solid of 1 and C.sub.1 -C.sub.6 alkyl esters thereof in acceptable yields. Finally, the synthetic process of this invention includes crystalline intermediates to provide both enrichment and purification of the desired product.
This invention provides a highly desirable stable crystalline (2S,3R,4R)([[2-[[4-(3-hydroxyphenyl)-3,4-dimethyl-1 -piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]acetic acid (1) which is the dihydrate.
The new crystalline intermediates and crystallization method are particularly important for the commercial development of the pharmaceutically active 3-4,4-trisubstituted-piperidinyl-N-alkylcarboxylates (18 and 18a infra.).